Environmental factors may affect aging, for example, overexposure to ultraviolet radiation accelerates skin aging. Different parts of the body may age at different rates. Two organisms of the same species can also age at different rates, making biological aging and chronological aging distinct concepts.

In 2013, a group of scientists defined nine hallmarks of aging that are common between organisms with emphasis on mammals: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication.[2]Aging is characterized by the declining ability to respond to stress, increased homeostatic imbalance, and increased risk of aging-associated diseases including cancer and heart disease. Aging has been defined as "a progressive deterioration of physiological function, an intrinsic age-related process of loss of viability and increase in vulnerability."[3]

The environment induces damage at various levels, e.g. damage to DNA, and damage to tissues and cells by oxygen radicals (widely known as free radicals), and some of this damage is not repaired and thus accumulates with time. Cloning from somatic cells rather than germ cells may begin life with a higher initial load of damage. Dolly the sheep died young from a contagious lung disease, but data on an entire population of cloned individuals would be necessary to measure mortality rates and quantify aging.

The evolutionary theorist George Williams wrote, "It is remarkable that after a seemingly miraculous feat of morphogenesis, a complex metazoan should be unable to perform the much simpler task of merely maintaining what is already formed."[4]

Differences rates of aging, i.e. different speeds with which mortality increases with age, correspond to different maximum life span among species. For example, a mouse is elderly at 3 years while a human is elderly at 80 years.[5]

Almost all organisms senesce, including bacteria which have asymmetries between "mother" and "daughter" cells upon cell division, with the mother cell experiencing aging, while the daughter is rejuvenated.[citation needed] Senescence has been so far undetectable in a handful of species (negligible senescence), such as those in the genus Hydra. Planarian flatworms have "apparently limitless telomere regenerative capacity fueled by a population of highly proliferative adult stem cells."[6] These organisms may be biologically immortal, meaning not that they do not die, but that their death rate does not increase with age. Some species exhibit "negative senescence", in which fecundity increases and/or mortality falls with age, due to the advantages of increased body size with age.[7]

Natural selection can support lethal and harmful alleles, if their effects are felt after reproduction. The geneticist J. B. S. Haldane wondered why the dominant mutation that causes Huntington's disease remained in the population, and why natural selection had not eliminated it. The onset of this neurological disease is (on average) at age 45 and is invariably fatal within 10–20 years. Haldane assumed that, in human prehistory, few survived until age 45. Since few were alive at older ages and their contribution to the next generation was therefore small relative to the large cohorts of younger age groups, the force of selection against such late-acting deleterious mutations was correspondingly small. Therefore, a genetic load of late-acting deleterious mutations could be substantial at mutation-selection balance. This concept came to be known as the selection shadow.[8]

Peter Medawar formalised this observation in his mutation accumulation theory of aging.[9][10] "The force of natural selection weakens with increasing age—even in a theoretically immortal population, provided only that it is exposed to real hazards of mortality. If a genetic disaster... happens late enough in individual life, its consequences may be completely unimportant". The 'real hazards of mortality' such as predation, disease, and accidents, are known 'extrinsic mortality', and mean that even a population with negligible senescence will have fewer individuals alive in older age groups.

Another evolutionary theory of aging was proposed by George C. Williams[11] and involves antagonistic pleiotropy. A single gene may affect multiple traits. Some traits that increase fitness early in life may also have negative effects later in life. But, because many more individuals are alive at young ages than at old ages, even small positive effects early can be strongly selected for, and large negative effects later may be very weakly selected against. Williams suggested the following example: Perhaps a gene codes for calcium deposition in bones, which promotes juvenile survival and will therefore be favored by natural selection; however, this same gene promotes calcium deposition in the arteries, causing negative atherosclerotic effects in old age. Thus, harmful biological changes in old age may result from selection for pleiotropic genes that are beneficial early in life but harmful later on. In this case, selection pressure is relatively high when Fisher's reproductive value is high and relatively low when Fisher's reproductive value is low.

An example of antagonistic pleiotropy may be the trade-off between investing resources in reproduction, rather than maintenance of the body – the "Disposable Soma" theory.[12] This theory states that resources can be allocated towards somatic maintenance and reproduction, such as in aging being a resource allocation to somatic maintenance rather than reproduction.[13]

In most multicellular species, somatic cells eventually experience replicative senescence and are unable to divide. This can prevent highly mutated cells from becoming cancerous. In culture, fibroblasts can reach a maximum of 50 cell divisions; this maximum is known as the Hayflick limit.[16] Replicative senescence is the result of telomere shortening that ultimately triggers a DNA damage response. Cells can also be induced to senesce via DNA damage in response to elevated reactive oxygen species (ROS), activation of oncogenes and cell-cell fusion, independent of telomere length.

The cellular senescence theory of aging posits that organismal aging is a consequence of the accumulation of less physiological useful senescent cells. In agreement with this, the experimental elimination of senescent cells from transgenic progeroid mice[17] and non-progeroid, naturally-aged mice[18][19][20] led to greater resistance against aging-associated diseases. Ectopic expression of the embryonic transcription factor, NANOG, is shown to reverse senescence and restore the proliferation and differentiation potential of senescent stem cells.[21][22][23][24][25]

In many organisms, there is asymmetric cell division, e.g. a stem cell dividing to produce one stem cell and one non-stem cell. The cellular debris that cells accumulate is not evenly divided between the new cells when they divide. Instead more of the damage is passed to one of the cells, leaving the other cell rejuvenated.[30] One lineage then undergoes cellular senescence faster than the other.

Cancer cells avoid replicative senescence to become immortal. In about 85% of tumors, this evasion of cellular senescence is the result of up-activation of their telomerase genes.[31]

Senescent cells within a multicellular organism can be purged by competition between cells, but this increases the risk of cancer. This leads to an inescapable dilemma between two possibilities - the accumulation of physiologically useless senescent cells, and cancer - both of which lead to increasing rates of mortality with age.[1]

While there may be some validity to the idea that for various types of specific damage detailed below that are by-products of metabolism, all other things being equal, a fast metabolism may reduce lifespan, in general this theory does not adequately explain the differences in lifespan either within, or between, species. Calorically restricted animals process as much, or more, calories per gram of body mass, as their ad libitum fed counterparts, yet exhibit substantially longer lifespans.[citation needed] Similarly, metabolic rate is a poor predictor of lifespan for birds, bats and other species that, it is presumed, have reduced mortality from predation, and therefore have evolved long lifespans even in the presence of very high metabolic rates.[33] In a 2007 analysis it was shown that, when modern statistical methods for correcting for the effects of body size and phylogeny are employed, metabolic rate does not correlate with longevity in mammals or birds.[34] (For a critique of the Rate of Living Hypothesis see Living fast, dying when?[35])

With respect to specific types of chemical damage caused by metabolism, it is suggested that damage to long-lived biopolymers, such as structural proteins or DNA, caused by ubiquitous chemical agents in the body such as oxygen and sugars, are in part responsible for aging. The damage can include breakage of biopolymer chains, cross-linking of biopolymers, or chemical attachment of unnatural substituents (haptens) to biopolymers.

Sugars such as glucose and fructose can react with certain amino acids such as lysine and arginine and certain DNA bases such as guanine to produce sugar adducts, in a process called glycation. These adducts can further rearrange to form reactive species, which can then cross-link the structural proteins or DNA to similar biopolymers or other biomolecules such as non-structural proteins. People with diabetes, who have elevated blood sugar, develop senescence-associated disorders much earlier than the general population, but can delay such disorders by rigorous control of their blood sugar levels. There is evidence that sugar damage is linked to oxidant damage in a process termed glycoxidation.

If different individuals age at different rates, then fecundity, mortality, and functional capacity might be better predicted by biomarkers than by chronological age.[39] However, graying of hair,[40]skin wrinkles and other common changes seen with aging are not better indicators of future functionality than chronological age. Biogerontologists have continued efforts to find and validate biomarkers of aging, but success thus far has been limited. Levels of CD4 and CD8 memory T cells and naive T cells have been used to give good predictions of the expected lifespan of middle-aged mice.[41]

There is interest in an epigenetic clock as a biomarker of aging, based on its ability to predict human chronological age.[42] Basic blood biochemistry and cell counts can also be used to accurately predict the chronological age.[43] It is also possible to predict the human chronological age using the transcriptomic aging clocks.[44]

Gene expression is imperfectly controlled, and it is possible that random fluctuations in the expression levels of many genes contribute to the aging process as suggested by a study of such genes in yeast.[45] Individual cells, which are genetically identical, nonetheless can have substantially different responses to outside stimuli, and markedly different lifespans, indicating the epigenetic factors play an important role in gene expression and aging as well as genetic factors.